Multi-target effects of novel synthetic coumarin derivatives protecting aβ-gfp sh-sy5y cells against aβ toxicity

Ching Chia Huang, Kuo Hsuan Chang, Ya Jen Chiu, Yi Ru Chen, Tsai Hui Lung, Hsiu Mei Hsieh-Li, Ming Tsan Su, Ying Chieh Sun, Chiung Mei Chen*, Wenwei Lin, Guey Jen Lee-Chen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Alzheimer’s disease (AD) is a common neurodegenerative disease presenting with pro-gressive memory and cognitive impairments. One of the pathogenic mechanisms of AD is attributed to the aggregation of misfolded amyloid β (Aβ), which induces neurotoxicity by reducing the expression of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase B (TRKB) and increasing oxidative stress, caspase-1, and acetylcholinesterase (AChE) activities. Here, we have found the potential of two novel synthetic coumarin derivatives, ZN014 and ZN015, for the inhibition of Aβ and neuroprotection in SH-SY5Y neuroblastoma cell models for AD. In SH-SY5Y cells expressing the GFP-tagged Aβ-folding reporter, both ZN compounds reduced Aβ aggregation, oxidative stress, activities of caspase-1 and AChE, as well as increased neurite outgrowth. By activating TRKB-mediated extracellular signal-regulated kinase (ERK) and AKT serine/threonine kinase 1 (AKT) signaling, these two ZN compounds also upregulated the cAMP-response-element binding protein (CREB) and its downstream BDNF and anti-apoptotic B-cell lymphoma 2 (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of ZN014 and ZN015. A parallel artificial membrane permeability assay showed that ZN014 and ZN015 could be characterized as blood–brain barrier permeable. Our results suggest ZN014 and ZN015 as novel therapeutic candidates for AD and demonstrate that ZN014 and ZN015 reduce Aβ neurotoxicity via pleiotropic mechanisms.

Original languageEnglish
Article number3095
JournalCells
Volume10
Issue number11
DOIs
Publication statusPublished - 2021 Nov

Keywords

  • Alzheimer’s disease
  • Coumarins
  • Neuroprotection
  • TRKB agonist
  • Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

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